tbuckley/cabot-search huggingface dataset:
Cancer-associated fibroblasts facilitate premetastatic niche formation through lncRNA SNHG5-mediated angiogenesis and vascular permeability in breast cancer
Authors: Huan Zeng, Yixuan Hou, Xinyue Zhou, Lei Lang, Haojun Luo, Yan Sun, Xueying Wan, Taixian Yuan, Rui Wang, Yongcan Liu, Rui Tang, Shaojie Cheng, Ming Xu, Manran Liu
Journal: Theranostics (2022)

Background: Metastasis is the leading cause of death in patients with breast cancer (BC). Primary tumors create a premetastatic niche (PMN) in secondary organs for subsequent metastases. Cancer-associated fibroblasts (CAFs) are a predominant stromal component in the tumor microenvironment and serve as a major contributor to tumor metastasis. However, the function and mechanism of primary CAFs in the premetastatic niche of secondary organs remain unclear in BC. Methods: We investigated the expression profiles of lncRNAs in pairs of CAFs and NFs derived from breast tumor tissues using lncRNA microarray. The expression levels of lncSNHG5, ZNF281, IGF2BP2, CCL2 and CCL5 were assessed by qRT-PCR; the protein levels of related genes (e.g., ZNF281, IGF2BP2, CCL2, and CCL5) were analyzed using western blotting and/or ELISA in primary and immortalized CAFs and clinical samples. Tubule formation and three-dimensional sprouting assays and tissue fluorescence staining were conducted to investigate angiogenesis. In vitro permeability assays, trans-endothelial invasion assays, in vivo permeability assays and tissue fluorescence staining were conducted to examine vascular permeability. The regulatory mechanism of lncSNHG5 was investigated by RNA sequencing, fluorescent in situ hybridization, cellular fractionation assay, mass spectrometry, RNA pull-down, RNA immunoprecipitation, gene-specific m6A assay, chromatin immunoprecipitation, dual luciferase reporter assay and actinomycin D treatment in CAFs and NFs. Results: LncSNHG5 was highly expressed in breast CAFs and played an essential role in premetastatic niche formation by promoting angiogenesis and vascular leakiness through regulation of ZNF281 in CAFs. lncSNHG5 enhanced ZNF281 mRNA stability by binding with the m6A reader IGF2BP2. Enhanced ZNF281 transcriptionally regulated CCL2 and CCL5 expression to activate P38 MAPK signaling in endothelial cells. High CCL2 and CCL5 expression was associated with tumor metastasis and poor prognosis in BC patients. The inhibitors RS102895, marasviroc and cenicriviroc inhibited angiogenesis and vascular permeability in the PMN by blocking the binding of CCL2/CCR2 and CCL5/CCR5. The lncSNHG5-ZNF281-CCL2/CCL5 signaling axis plays an essential role in inducing premetastatic niche formation to promote BC metastasis. Conclusions: Our work demonstrates that lncSNHG5 and its downstream signaling ZNF281-CCL2/CCL5 in CAFs play a crucial role in premetastatic niche formation in breast cancer and may serve as potential targets for the diagnosis and treatment of BC metastasis.
N6-methyladenosine-associated prognostic pseudogenes contribute to predicting immunotherapy benefits and therapeutic agents in head and neck squamous cell carcinoma
Authors: Liqiang Tan, Yali Qin, Ruiling Xie, Tianliang Xia, Xiaotong Duan, Lan Peng, Rui You, Youping Liu, Xiong Zou, Mengxia Zhang, Mei Lin, Mingyuan Chen
Journal: Theranostics (2022)

Rationale: N6-methyladenosine (m 6 A) is involved in critical cancerous processes.Pseudogenes play various roles in carcinogenesis and progression.However, the functional roles of m 6 A-associated pseudogenes in head and neck squamous cell carcinoma (HNSCC) are largely unknown.Methods: We systematically analyzed the mRNA profile of 24 m 6 A regulators and 13931 pseudogenes from The Cancer Genome Atlas HNSCC dataset and ultimately identified 10 m 6 A-associated prognostic pseudogenes, which were validated in the Gene Expression Omnibus and our hospital datasets.Based on the risk score of m 6 A-associated pseudogenes, comprehensive analytical frameworks and experimental validation were implemented among pseudogene-defined low-/high-risk subtypes.Results: Here, we found expression pattern of m 6 A-associated pseudogenes was significantly associated with infiltrating immune cell compositions, and the expression of antitumor immune response markers, including T cell exhaustion, antigen presentation, interferon, and kinase genes.The m 6 A-associated pseudogenes, which had dramatic m 6 A peaks and higher m 6 A levels, could regulate the expression of targeted immune-involved genes through miRNAs.We experimentally validate the oncogene PDIA3P1, and tumor-suppressor RRN3P3, which promote the RNA and protein expression of their targeted immune-involved genes AKT1 and EZH2 via miR-34a-5p and miR-26b-5p, respectively.Moreover, HNSCC patients in the high-risk subtype could benefit more from immune checkpoint inhibitors therapy.Furthermore, doxorubicin and topotecan were considered to hold the most promising therapeutic potential robustly in silico evidence and in vitro experiments for HNSCC patients in the high-risk subtype.Conclusions: Our discovery revealed that the 10 m 6 A-associated prognostic pseudogenes significantly contribute to predicting immunotherapy benefits and therapeutic agents, which might bring some potential implications for both immunotherapy and chemotherapy in HNSCC.
Association of Early Progression Independent of Relapse Activity With Long-term Disability After a First Demyelinating Event in Multiple Sclerosis
Authors: Carmen Tur, Pere Carbonell-Mirabent, Álvaro Cobo-Calvo, Susana Otero-Romero, Georgina Arrambide, Luciana Midaglia, Joaquín Castilló, Ángela Vidal-Jordana, Breogán Rodríguez-Acevedo, Ana Zabalza, Ingrid Galán, Carlos Nos, Annalaura Salerno, Cristina Auger, Deborah Pareto, Manuel Comabella, Jordi Río, Jaume Sastre-Garriga, Àlex Rovira, Mar Tintoré, Xavier Montalban
Journal: JAMA Neurology (2022)

Progression independent of relapse activity (PIRA) is the main event responsible for irreversible disability accumulation in relapsing multiple sclerosis (MS).To investigate clinical and neuroimaging predictors of PIRA at the time of the first demyelinating attack and factors associated with long-term clinical outcomes of people who present with PIRA.This cohort study, conducted from January 1, 1994, to July 31, 2021, included patients with a first demyelinating attack from multiple sclerosis; patients were recruited from 1 study center in Spain. Patients were excluded if they refused to participate, had alternative diagnoses, did not meet protocol requirements, had inconsistent demographic information, or had less than 3 clinical assessments.Exposures included (1) clinical and neuroimaging features at the first demyelinating attack and (2) presenting PIRA, ie, confirmed disability accumulation (CDA) in a free-relapse period at any time after symptom onset, within (vs after) the first 5 years of the disease (ie, early/late PIRA), and in the presence (vs absence) of new T2 lesions in the previous 2 years (ie, active/nonactive PIRA).Expanded Disability Status Scale (EDSS) yearly increase rates since the first attack and adjusted hazard ratios (HRs) for predictors of time to PIRA and time to EDSS 6.0.Of the 1128 patients (mean [SD] age, 32.1 [8.3] years; 781 female individuals [69.2%]) included in the study, 277 (25%) developed 1 or more PIRA events at a median (IQR) follow-up time of 7.2 (4.6-12.4) years (for first PIRA). Of all patients with PIRA, 86 of 277 (31%) developed early PIRA, and 73 of 144 (51%) developed active PIRA. Patients with PIRA were slightly older, had more brain lesions, and were more likely to have oligoclonal bands than those without PIRA. Older age at the first attack was the only predictor of PIRA (HR, 1.43; 95% CI, 1.23-1.65; P < .001 for each older decade). Patients with PIRA had steeper EDSS yearly increase rates (0.18; 95% CI, 0.16-0.20 vs 0.04; 95% CI, 0.02-0.05; P < .001) and an 8-fold greater risk of reaching EDSS 6.0 (HR, 7.93; 95% CI, 2.25-27.96; P = .001) than those without PIRA. Early PIRA had steeper EDSS yearly increase rates than late PIRA (0.31; 95% CI, 0.26-0.35 vs 0.13; 95% CI, 0.10-0.16; P < .001) and a 26-fold greater risk of reaching EDSS 6.0 from the first attack (HR, 26.21; 95% CI, 2.26-303.95; P = .009).Results of this cohort study suggest that for patients with multiple sclerosis, presenting with PIRA after a first demyelinating event was not uncommon and suggests an unfavorable long-term prognosis, especially if it occurs early in the disease course.
Ninj2 regulates Schwann cells development by interfering laminin-integrin signaling
Authors: Yuxia Sun, Xiang Chen, Cen Yue, Wenyi Yang, Shu Zhang, Zhimin Ou, Ying Chen
Journal: Theranostics (2022)

Rationale: Myelin sheath is an important structure to maintain normal functions of the nerves.Nerve Injury-Induced Protein 2 (Ninj2) was found upregulated in Schwann cells (SC) upon injury.However, whether and how Ninj2 plays a role in myelination remain unknown.Methods: In this study, we use transmission electron microscope imaging, immunofluorescent imaging, and behavioral tests to show the effects of Ninj2 on myelination and remyelination in peripheral nervous system (PNS) of SC-specific Ninj2 knockout mice (Dhh cre/+ ;Ninj2 fl/fl ).For mechanism studies, we use RNA-Seq analysis to show the Ninj2-related pathways, and co-immunoprecipitation/mass-spectrometry to identify the Ninj2-interacting proteins in SCs.Furthermore, we evaluate the effect of integrin inhibitor GRGDSP during remyelination.Results: Ninj2 negatively regulates SC development.Ninj2-deficient mice exhibit precocious myelination phenotype, as well as the accelerated remyelination process after sciatic nerve injury.Loss of Ninj2 promotes myelination by promoting SC proliferation to augment its population.Mechanistically, Ninj2 interacted with ITGB1 on SC membrane, which inhibits laminin-integrin signaling.Removal of Ninj2 induces the activity of laminin-integrin signaling, resulting in the improved myelination in the Dhh cre/+ ;Ninj2 fl/fl mice.Inhibition of laminin-integrin signaling by integrin inhibitor GRGDSP sufficiently delays the remyelination process in the Dhh cre/+ ;Ninj2 fl/fl mice with sciatic nerve injury.Conclusion: Our study found Ninj2 as a negative regulator in the network controlling myelination in the PNS.
Molecular Clusters and Tumor-Immune Drivers of IgM Monoclonal Gammopathies
Authors: Patrizia Mondello, Jonas Paludo, Joseph P. Novak, Kerstin Wenzl, Zhi-Zhang Yang, Shahrzad Jalali, Jordan E. Krull, Esteban Braggio, Surendra Dasari, Michelle K. Manske, Jithma A. Abeykoon, Vivekananda Sarangi, Prashant Kapoor, Aneel Paulus, Craig B. Reeder, Sikander Ailawadhi, Asher A. Chanan-Khan, Robert A. Kyle, Morie A. Gertz, Anne J. Novak, Stephen M. Ansell
Journal: Clinical Cancer Research (2022)

IgM monoclonal gammopathy of undetermined significance (MGUS) and Waldenström macroglobulinemia (WM) represent a disease spectrum with highly varied therapeutic management, ranging from observation to chemoimmunotherapy. The current classification relies solely on clinical features and does not explain the heterogeneity that exists within each of these conditions. Further investigation is warranted to shed light on the biology that may account for the clinical differences.We used bone marrow (BM) clonal CD19+ and/or CD138+ sorted cells, matched BM supernatant, and peripheral blood serum from 32 patients (7 MGUS, 25 WM) to perform the first multi-omics approach including whole-exome sequencing, RNA sequencing, proteomics, metabolomics, and mass cytometry.We identified three clusters with distinct pathway activation, immune content, metabolomic, and clinical features. Cluster 1 included only patients with WM and was characterized by transcriptional silencing of genes involved in cell cycle and immune response, enrichment of mitochondrial metabolism, infiltration of senescent T effector memory cells, and aggressive clinical behavior. Genetic/structural alterations of TNFAIP3 were distinct events of this cluster. Cluster 2 comprised both MGUS and WM patients with upregulation of inflammatory response, senescence and glycolysis signatures, increased activated T follicular helper and T regulatory cells, and indolent clinical behavior. Cluster 3 also included both MGUS and WM patients and exhibited intermediate features, including proliferative and inflammatory signaling, as well as glycolysis and mitochondrial metabolism.We have identified three distinct molecular clusters, suggesting a potential biologic classification that may have therapeutic implications.
Protein Profiling in Presymptomatic Individuals Separates Myeloperoxidase–Antineutrophil Cytoplasmic Antibody and Proteinase 3–Antineutrophil Cytoplasmic Antibody Vasculitides
Authors: Mikael Brink, Ewa Berglin, Aladdin J. Mohammad, Anders Lundquist, Inger Gjertsson, Andrey Alexeyenko, Kristina Lejon, Solbritt Rantapää‐Dahlqvist
Journal: Arthritis & Rheumatology (2022)

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a chronic relapsing condition with unknown etiology. To gain insight into the molecular processes underlying the disease, we examined biomarkers in blood samples collected prior to symptom onset.The National Patient Register and Cause of Death register were searched for AAV-related International Classification of Diseases, Ninth Revision and Tenth Revision codes and linked to the registers from 5 biobanks. Eighty-five AAV patients with samples predating symptom onset of AAV were identified. For each case of AAV, 2 matched controls were included. Proteinase 3 (PR3)-ANCA and myeloperoxidase (MPO)-ANCA expression levels were analyzed using enzyme-linked immunosorbent assays. Using an Olink Inflammation panel, 73 of 92 proteins were included after quality control. Data were replicated in a second cohort of 48 presymptomatic individuals and 96 controls.Of the 20 proteins with the lowest P values in the original cohort, 7 were replicated in the second cohort and 5 proteins were found to be significant between the groups in a meta-analysis. Eleven different pathways were identified in network enrichment analyses and were found to be significant in both cohorts. Stratification of samples obtained ≤5 years before symptom onset showed significant levels of CCL23, vascular endothelial growth factor A, and hepatocyte growth factor, which were also increased at borderline significant levels in the replication cohort (interleukin-6 was found to be significantly increased in the replication cohort). In presymptomatic AAV patients, 6 proteins were associated with MPO-ANCA positivity, and 7 proteins were associated with PR3-ANCA positivity.To our knowledge, this is the first study to identify protein markers preceding symptom onset in AAV patients. These findings set the stage for further research into the underlying cellular and molecular mechanisms in the pathogenesis of AAV and the diversification of patients into PR3-ANCA+ and MPO-ANCA+ subphenotypes.
Elucidating the Interactome of G Protein-Coupled Receptors and Receptor Activity-Modifying Proteins
Authors: Ilana B. Kotliar, Emily Lorenzen, Jochen M. Schwenk, Debbie L. Hay, Thomas P. Sakmar
Journal: Pharmacological Reviews (2022)

G protein-coupled receptors (GPCRs) are known to interact with several other classes of integral membrane proteins that modulate their biology and pharmacology. However, the extent of these interactions and the mechanisms of their effects are not well understood. For example, one class of GPCR-interacting proteins, receptor activity-modifying proteins (RAMPs), comprise three related and ubiquitously expressed single-transmembrane span proteins. The RAMP family was discovered more than two decades ago, and since then GPCR-RAMP interactions and their functional consequences on receptor trafficking and ligand selectivity have been documented for several secretin (class B) GPCRs, most notably the calcitonin receptor-like receptor. Recent bioinformatics and multiplexed experimental studies suggest that GPCR-RAMP interactions might be much more widespread than previously anticipated. Recently, cryo-electron microscopy has provided high-resolution structures of GPCR-RAMP-ligand complexes, and drugs have been developed that target GPCR-RAMP complexes. In this review, we provide a summary of recent advances in techniques that allow the discovery of GPCR-RAMP interactions and their functional consequences and highlight prospects for future advances. We also provide an up-to-date list of reported GPCR-RAMP interactions based on a review of the current literature. SIGNIFICANCE STATEMENT: Receptor activity-modifying proteins (RAMPs) have emerged as modulators of many aspects of G protein-coupled receptor (GPCR)biology and pharmacology. The application of new methodologies to study membrane protein-protein interactions suggests that RAMPs interact with many more GPCRs than had been previously known. These findings, especially when combined with structural studies of membrane protein complexes, have significant implications for advancing GPCR-targeted drug discovery and the understanding of GPCR pharmacology, biology, and regulation.
Pharmacological Modulation of the Crosstalk between Aberrant Janus Kinase Signaling and Epigenetic Modifiers of the Histone Deacetylase Family to Treat Cancer
Authors: Al-Hassan M. Mustafa, Oliver H. Krämer
Journal: Pharmacological Reviews (2022)

Hyperactivated Janus kinase (JAK) signaling is an appreciated drug target in human cancers. Numerous mutant JAK molecules as well as inherent and acquired drug resistance mechanisms limit the efficacy of JAK inhibitors (JAKi). There is accumulating evidence that epigenetic mechanisms control JAK-dependent signaling cascades. Like JAKs, epigenetic modifiers of the histone deacetylase (HDAC) family regulate the growth and development of cells and are often dysregulated in cancer cells. The notion that inhibitors of histone deacetylases (HDACi) abrogate oncogenic JAK-dependent signaling cascades illustrates an intricate crosstalk between JAKs and HDACs. Here, we summarize how structurally divergent, broad-acting as well as isoenzyme-specific HDACi, hybrid fusion pharmacophores containing JAKi and HDACi, and proteolysis targeting chimeras for JAKs inactivate the four JAK proteins JAK1, JAK2, JAK3, and tyrosine kinase-2. These agents suppress aberrant JAK activity through specific transcription-dependent processes and mechanisms that alter the phosphorylation and stability of JAKs. Pharmacological inhibition of HDACs abrogates allosteric activation of JAKs, overcomes limitations of ATP-competitive type 1 and type 2 JAKi, and interacts favorably with JAKi. Since such findings were collected in cultured cells, experimental animals, and cancer patients, we condense preclinical and translational relevance. We also discuss how future research on acetylation-dependent mechanisms that regulate JAKs might allow the rational design of improved treatments for cancer patients. <h3>Significance Statement</h3> Reversible lysine-<b>ɛ</b>-N acetylation and deacetylation cycles control phosphorylation-dependent Janus kinase–signal transducer and activator of transcription signaling. The intricate crosstalk between these fundamental molecular mechanisms provides opportunities for pharmacological intervention strategies with modern small molecule inhibitors. This could help patients suffering from cancer.
Dopamine, Immunity, and Disease
Authors: Breana Channer, Stephanie M. Matt, Emily A. Nickoloff-Bybel, Vasiliki Pappa, Yash Agarwal, Jason Wickman, Peter J. Gaskill
Journal: Pharmacological Reviews (2022)

The neurotransmitter dopamine is a key factor in central nervous system (CNS) function, regulating many processes including reward, movement, and cognition. Dopamine also regulates critical functions in peripheral organs, such as blood pressure, renal activity, and intestinal motility. Beyond these functions, a growing body of evidence indicates that dopamine is an important immunoregulatory factor. Most types of immune cells express dopamine receptors and other dopaminergic proteins, and many immune cells take up, produce, store, and/or release dopamine, suggesting that dopaminergic immunomodulation is important for immune function. Targeting these pathways could be a promising avenue for the treatment of inflammation and disease, but despite increasing research in this area, data on the specific effects of dopamine on many immune cells and disease processes remain inconsistent and poorly understood. Therefore, this review integrates the current knowledge of the role of dopamine in immune cell function and inflammatory signaling across systems. We also discuss the current understanding of dopaminergic regulation of immune signaling in the CNS and peripheral tissues, highlighting the role of dopaminergic immunomodulation in diseases such as Parkinson’s disease, several neuropsychiatric conditions, neurologic human immunodeficiency virus, inflammatory bowel disease, rheumatoid arthritis, and others. Careful consideration is given to the influence of experimental design on results, and we note a number of areas in need of further research. Overall, this review integrates our knowledge of dopaminergic immunology at the cellular, tissue, and disease level and prompts the development of therapeutics and strategies targeted toward ameliorating disease through dopaminergic regulation of immunity. <h3>Significance Statement</h3> Canonically, dopamine is recognized as a neurotransmitter involved in the regulation of movement, cognition, and reward. However, dopamine also acts as an immune modulator in the central nervous system and periphery. This review comprehensively assesses the current knowledge of dopaminergic immunomodulation and the role of dopamine in disease pathogenesis at the cellular and tissue level. This will provide broad access to this information across fields, identify areas in need of further investigation, and drive the development of dopaminergic therapeutic strategies.